U.S. Pat. No. 4,849,431 (Sugimoto et al.) discloses compounds of the formula: EQU R.sup.1 --X--A--R.sup.2
wherein:
R.sup.1 denotes a univalent group derived from one selected among substituted or unsubstituted benzene, pyridine, pyrazine, indole, anthraquinone, quinoline, substituted or unsubstituted phthalimide PA1 X denotes a group of the formula --(CH.sub.2).sub.n --, --O(CH.sub.2).sub.n --, --S(CH.sub.2).sub.n --, --NH(CH.sub.2).sub.n --, --SO.sub.2 NH(CH.sub.2).sub.n --, --NH--C(.dbd.O)--(CH.sub.2).sub.n --, --NH(CH.sub.2).sub.n --C(.dbd.O)--, --C(.dbd.O)--O(CH.sub.2).sub.n --, --CH.sub.2 NH(CH.sub.2).sub.n --, --C(.dbd.O)--N(R.sup.3)--(CH.sub.2).sub.n, or --OCH.sub.2 --CH(OH)--CH.sub.2 -- (in all the above formulas, n is an integer of 1 through 7 and R.sup.3 represents a lower alkyl group or a benzyl group); PA1 ring A denotes a group of the formula, ##STR2## R.sup.2 denotes hydrogen, lower alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzoyl, pyridyl, 2 -hydroxyethyl, pyridylmethyl or a group of the formula ##STR3## (wherein Z represents a halogen atom). PA1 R.sup.1 and R.sup.2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano, or nitro; PA1 Y is a single bond or a divalent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclusive. PA1 R.sup.2 and R.sup.3, which may be the same or different, are hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro, hydroxy, amino, monoalkylamino or dialkylamino. PA1 R.sup.2 is selected from hydrogen, halogen, alkyl having 1, 2, or 3 carbon atoms, alkoxy having 1, 2, or 3 carbon atoms, and trifluoromethyl.
including specifically: ##STR1## pyridinecarboxylic acid imide, pyridine N-oxide, pyrazinedicarboxylic acid imide, substituted or unsubstituted quinazolinedione and pyromerylimide;
These compounds are disclosed as being useful in the treatment and prevention of dementia and sequelae of cerebrovascular disease.
U.S. Pat. No. 4,495,194 and U.S. Pat. No. 4,600,758 describe 3-oxoisoindole derivatives having antihypertensive and/or diuretic properties characterized by a compound of the formula: ##STR4## wherein: X is halogen or trifluoromethyl;
U.S. Pat. No. 4,495,194 and U.S. Pat. No. 4,600,758 also describe the following compounds as intermediates: ##STR5## GB 1,425,578 discloses compounds of the formula: ##STR6## and their pharmaceutically acceptable acid addition salts, wherein: R.sup.1 is hydrogen, alkyl, aralkyl or alkyl substituted by a heterocyclyl group;
These compounds are disclosed as having anti-convulsant activity and in some cases, anti-inflammatory activity or anti-arrhythmic activity.
U.S. Pat. No. 4,289,781 (Bengtson et al.) describes compounds useful for the treatment of psychoses in man such compounds having the formula: ##STR7## wherein: R.sup.0 and R.sup.1 are the same or different and are each selected from hydrogen, halogen, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1, 2, or 3 carbon atoms, and trifluoromethyl; and
The compounds described in the prior art, cited above, do not show the sigma receptor selectivity demonstrated by the compounds of the present invention. It is this sigma receptor selectivity which makes the compounds of the present invention advantageous over compounds of the prior art. Traditionally, antipsychotic agents have been potent dopamine receptor antagonists. For example, phenothiazines such as chlorpromazine and most butyrophenones such as haloperidol are potent dopamine receptor antagonists. These dopamine receptor antagonists are associated with a high incidence of side effects, particularly Parkinson-like motor effects or extra-pyramidal side-effects (EPS), and dyskinesias including tardive dyskinesias at high doses. Many of these side effects are not reversible even after the dopamine receptor antagonist agent is discontinued.
The present invention is related to antipsychotic agents which are selective antagonists for the sigma receptor. Unlike dopamine receptor blockers known in the art, the compounds of the present invention have low potential for the typical movement disorder side-effects associated with the dopamine antagonist antipsychotic agents while they maintain the ability to antagonize aggressive behavior and antagonize hallucinogenic-induced behavior.